Gemcitabine HCl (2′,2′-difluorodeoxycytidine HCl, dFdC), marketed as Gemzar®, is a clinically approved anticancer drug for the treatment of a wide spectrum of cancers including pancreatic, non-small cell lung cancer, breast, bladder, head and neck, mesothelioma, cervical, and ovarian cancers. Gemcitabine is a polar deoxycytidine analog and requires nucleoside transporters to translocate across the cellular membrane. Gemcitabine is known to enter cells principally through Equilibrative Nucleoside Transporter 1 (ENT1). Gemcitabine first needs to be phosphorylated to gemcitabine monophosphate (dFdCMP) by deoxycytidine kinase (dCK), and dFdCMP is then subsequently phosphorylated by nucleotide kinases to di- and tri-phosphorylated gemcitabine (dFdCDP and dFdCTP, respectively) which are active metabolites of gemcitabine. Unfortunately, tumor cells often acquire gemcitabine resistance either during or after gemcitabine treatment.
Various derivatives of gemcitabine have been developed, for example, in attempts to improve in vitro performance and/or to expand therapeutic uses. Some such derivatives have been suggested for use in treating viral infections, including HCV. An estimated 170 million people throughout the world are infected with HCV. More than 70% of these individuals remain chronically infected for life, of which 15-20% eventually develops liver cirrhosis and hepatocellular carcinoma. The current therapy for HCV infections is the combination of ribavirin, interferon-α (IFN-α), and recently approved HCV inhibitors such as boceprevir, marketed as Victrelis® and telaprevir, marketed as Incivek®. Unfortunately, in addition to severe side effects in some cases, the sustained response rate of such therapies is less than desirable and may be genotype-dependent. Thus, there is a need in the art for new gemcitabine analogs that are effective and provide improvement for various applications.